Adjuvant Systemic Treatment for (ER)-Positive HER2-negative Breast Carcinoma in Women Over 70 According to Genomic Grade (GG): Chemotherapy + Endocrine Treatment Versus Endocrine Treatment

Breast Cancer Clinical Trial

— ASTER 70s  

Official title:

Adjuvant Systemic Treatment for Oestrogen-receptor (ER)-Positive HER2-negative Breast Carcinoma in Women Over 70 According to Genomic Grade (GG): Chemotherapy + Endocrine Treatment Versus Endocrine Treatment. A French UNICANCER Geriatric Oncology Group (GERICO) and Breast Group (UCBG) Multicentre Phase III Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01564056
• Other study ID #: GERICO11/PACS10
• Secondary ID: 2011-004744-22UC
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 12, 2012
• Est. completion date: March 2026

Study information

• Verified date: May 2024
• Source: UNICANCER
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to evaluate the benefit of adjuvant chemotherapy on overall survival for elderly patients with breast cancer, in a sub group with a high risk of relapse according to Genomic Grade test.

Description:

The purpose of this trial is to address the question of the added value of adjuvant chemotherapy on survival in 70+ BC patients with ER+ disease, deemed "at risk of relapse" (pN+ or pN0 with a high prognostic classifier, namely GG by RT-PCR) and planned to receive as well adjuvant endocrine treatment. This benefit will be weighed with the competition exerted by comorbidities on mortality.

As in many recently developed trials evaluating specific strategies for the elderly (e.g. CALGB 49907 (8); bevacizumab and colorectal cancer in the PRODIGE 20 elderly program supported by the PHRC 2010), the choice of chemotherapy regimen will be left to the investigator between 3 "standard" ones: TC x 4 (no anthracyclines), AC x 4 or MC x 4 (better cardiac tolerance), in order to obtain enrolment of a less highly selected population, more representative of the general population to the difference of the high selection classically observed in standard oncology trials.

In parallel, patients not included in the randomized part (whatever reason) and treated with adjuvant endocrine treatment only will be followed up as a separate observational cohort.

1. Screening All women 70+ having undergone surgery for invasive pN0 or pN+, ER+ HER2- BC, will be screened and invited to participate. Pre-selection will be possible pre-operatively.

2. Prognostic signature After having signed a written informed consent, the prognostic signature Genomic Grade (GG) will be assessed by RT-PCR.

3. Randomization (Group I) Only the patients with a Genomic Grade (GG) considered as high will be randomized (1:1): endocrine treatment only (Arm A) versus endocrine treatment + adjuvant chemotherapy (Arm B).

Randomization1:1 between arm A and B will be done using minimization stratified according to pN status (pN+ vs pN0), G8 (≤ vs > 14), and center.

Given (i) the high potential of less cardiotoxic regimen including liposomal formulations for anthracyclines or excluding anthracyclines and (ii) the wish to capture the whole population to depict the heterogeneity of ageing from 70, adjuvant chemotherapy (Arm B) will be left to the choice of investigator amongst 3 standard regimen of same duration, 4 cycles given every 3 weeks + primary prophylactic GCSF:

• AC = doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m²

• TC = docetaxel 75 mg/m² + cyclophosphamide 600 mg/m²

• MC = liposomal non pegylated doxorubicin (Myocet) 60 mg/m² + cyclophosphamide 600 mg/m²

4. Patients not randomized (Group II) Patients not randomized for any reason (low GG, randomization refusal or treatment refusal, etc.) will enter a surveillance program and will be able to participate to other specific geriatric studies (GERICO project to evaluate the impact of comprehensive geriatric assessment on quality of life, treatment administered and BC survival after 75 years; EORTC study to validate the scale specifically developed for elderly ELD15).

The Group II will present a triple interest and will participate, together with randomized patients, to achieve the following objectives:

• validation of the prognostic value of Genomic Grade and performance of the test in the elderly BC population, as compared to standardized routine histopathological parameters,

• translational studies to identify molecular signatures,

• collection of descriptive data including comorbidities and polymedication.

5. Endocrine treatment and radiotherapy In both Groups (I and II), the endocrine treatment will be left to the choice of the investigator (tamoxifen, aromatase inhibitor or sequential) and radiotherapy will follow standard guidelines.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1989
• Est. completion date: March 2026
• Est. primary completion date: April 11, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 70 Years and older

Eligibility

Inclusion Criteria:

• Women aged = 70 yo,

• Histologically proven invasive breast cancer (regardless of the type),

• Complete surgery performed before enrolment: radical modified mastectomy or breast conservative surgery, with either a sentinel lymph node procedure or axillary lymph node dissection,

• Any N status (pN+ or pN0),

• No clinically or radiologically detectable metastases (M0),

• Oestrogen receptor (ER)-positive, as defined by a = 10% tumor stained cells by immunohistochemistry (IHC),

• HER2 negative status (i.e. IHC score 0 or 1+, or IHC score 2+ and FISH/SISH/CISH negative),

• Normal haematological function: ANC = 1,500/mm3; platelets count = 100,000/mm3; haemoglobin > 9 g/dl,

• Normal hepatic function: total bilirubin = 1.25 ULN; ASAT and ALAT = 1.5 ULN; alkaline phosphatases = 3 ULN,

• Creatinine clearance (MDRD formula) = 40 mL/min,

• PS (ECOG) = 2,

• Patient able to comply with the protocol,

• Patients must have signed a written informed consent form prior to any study specific procedures, including the agreement for the use of archived tumoral material for genomic screening and data collection,

• Patients must be affiliated to a Social Health Insurance.

Exclusion Criteria:

• Any metastatic impairment, including homolateral sub-clavicular node involvement, regardless of its type,

• Any tumor = T4a (UICC1987) (cutaneous invasion, deep adherence, inflammatory breast cancer),

• ER-negative breast cancer (i.e. <10% tumor stained cells by IHC),

• HER2 overexpression, defined as IHC score 3+ or score 2+ and FISH/SISH/CISH positive,

• Any chemotherapy, hormonal therapy or radiotherapy for breast cancer before surgery,

• PS (ECOG) = 3,

• Any specific contra-indication to the study drugs (including but not limited to hypersensitivity to the study drugs or their components),

• Patient deprived of freedom or under tutelage,

• Patient unable to comply with the required medical follow-up for geographic, social or psychological reasons.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• HORMONOTHERAPY
Hormonotherapy will be administered during 5 years following chemotherapy when allocated. (Tamoxifen, aromatase inhibitor or sequential hormonotherapy) is left to the investigator judgement in both groups (I and II).
• CHEMOTHERAPY then HORMONOTHERAPY
CHEMOTHERAPY regimen will be chosen amongst the following ones: i) 4 cycles of TC (docetaxel + cyclophosphamide) Docetaxel 75 mg/m² IV infusion at hospital every 21 days Cyclophosphamide 600 mg/m² IV infusion at hospital every 21 days ii) 4 cycles of AC (doxorubicin + cyclophosphamide) Doxorubicin 60 mg/m² IV infusion at hospital every 21 days Cyclophosphamide 600 mg/m² IV infusion at hospital every 21 days iii) 4 cycles of MC (liposomal non pegylated doxorubicin [Myocet®]+ cyclophosphamide) Myocet® 60 mg/m² IV infusion at hospital every 21 days Cyclophosphamide 600 mg/m² IV infusion at hospital every 21 days HORMONOTHERAPY (Tamoxifen, aromatase inhibitor or sequential hormonotherapy) is left to the investigator judgement in both groups (I and II).

Locations

Country	Name	City	State
Belgium	Clinique du Sud Luxembourg	Arlon
Belgium	Cliniques universitaires Saint-Luc - UCL	Bruxelles
Belgium	Grand Hopital de Charleroi (GHdC)	Charleroi
Belgium	Hôpital INDC entité Jolimontoise	Haine-Saint-Paul
Belgium	Centre Hospitalier de l'Ardenne	Libramont
Belgium	CHC - Les Cliniques Saint-Joseph	Liege
Belgium	CHU Ambroise Paré	Mons
Belgium	Clinique et Maternité Sainte-Elisabeth	Namur
Belgium	Cliniques Saint-Pierre Ottignies	Ottignies
Belgium	Centre Hôspitalier de Wallonie Picarde (CHWAPI)	Tournai
Belgium	CHPLT Verviers	Verviers
Belgium	CHU Mont-Godinne	Yvoir
France	Clinique Claude Bernard	Albi
France	Centre Paul Papin	Angers
France	CH d'Ardèche méridionale	Aubenas
France	Institut Sainte Catherine	Avignon
France	Polyclinique Urbain V	Avignon
France	Hôpital Avicenne	Bobigny
France	Institut Bergonié	Bordeaux
France	CHU de Brest	Brest
France	Centre François Baclesse	Caen Cedex 05
France	Centre Hospitalier René Dubos	Cergy -pontoise
France	CH de Cholet	Cholet
France	Hôpital Antoine Béclère	Clamart
France	Centre Jean Perrin	Clermont Ferrand
France	Centre Hospitalier Alpes Léman	Contamine Sur Arve
France	Groupement Hospitalier Public du Sud de l'Oise - site de Creil	Creil
France	CHI de Créteil	Creteil
France	Hôpital Henri Mondor	Creteil
France	CH de Dax	DAX
France	Centre d'oncologie et de radiothérapie du Parc	Dijon
France	Centre Georges-François Leclerc	Dijon
France	CH Jean Monnet	Epinal
France	Clinique Sainte Marguerite	Hyeres
France	CHD de Vendée	La Roche Sur Yon
France	CH de Lagny sur Marne	Lagny Sur Marne
France	CH du Mans	Le Mans
France	Clinique Victor Hugo	Le Mans
France	Clinique Hartmann	Levallois-perret
France	Centre Oscar Lambret	Lille
France	CHU de Limoges	Limoges
France	Centre Hospitalier de Bretagne Sud	Lorient
France	Centre Léon Bérard	Lyon
France	CH de Mâcon - Les Chanaux	Mâcon
France	Institut Paoli-Calmettes	Marseille
France	Centre Hospitalier Intercommunal de Meulan - Les Mureaux	Meulan-en-Yvelines
France	CH Layné	Mont de Marsan
France	Clinique du Pont de Chaume	Montauban
France	Centre Val d'Aurelle - Paul Lamarque	Montpellier
France	Centre Antoine Lacassagne	Nice
France	CHR d'Orléans	Orleans
France	Groupe Hospitalier des Diaconesses - Croix Saint Simon	Paris
France	Groupe Hospitalier Paris St Joseph	Paris
France	Institut Curie - Hôpital Claudius Regaud	Paris
France	Polyclinique de Francheville	Perigueux
France	Centre Hospitalier Lyon Sud	Pierre Benite
France	CHU de Poitiers	Poitiers
France	CH de la Région d'Annecy	Pringy
France	Institut du Cancer Courlancy	Reims
France	Institut Jean Godinot	Reims
France	Centre Eugène Marquis	Rennes
France	CH de Rodez	Rodez
France	Centre Henri Becquerel	Rouen
France	Clinique Mathilde	Rouen
France	CHI Poissy Saint Germain	Saint Germain En Laye
France	CHP Saint Grégoire	Saint Gregoire
France	Institut de Cancérologie de la Loire	Saint Priest En Jarez
France	Institut Curie - Hôpital René Huguenin	Saint-cloud
France	ICO -Centre René Gauducheau	Saint-Herblain
France	Clinique Mutualiste de l'Estuaire	Saint-nazaire
France	RISSA Sarcelles (GCS Recherche & Innovation Santé Sarcelles)	Sarcelles
France	CH de Senlis	Senlis
France	Centre Paul Strauss	Strasbourg
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
France	Strasbourg Oncologie Libérale	Strasbourg
France	Hopitaux du Léman	Thonon-les-bains
France	CHI de Toulon - Hopital Sainte Musse	Toulon
France	Clinique Pasteur	Toulouse
France	Clinique Saint Jean du Languedoc	Toulouse
France	Institut Claudius Regaud	Toulouse
France	Centre Alexis Vautrin	Vandoeuvre Les Nancy
France	Centre Saint Yves	Vannes
France	CH Bretagne Atlantique	Vannes
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
UNICANCER

Countries where clinical trial is conducted

Belgium,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	The OS is defined as the interval between the date of randomization and the date of death from any cause.	Median follow-up = 4 years
Secondary	Specific overall survival	The specific OS is defined as the interval between the date of randomization and the date of death due to cancer. Alive patients or dead patients from another cause will be censored at the last follow-up	median follow-up = 4 years
Secondary	Disease-free survival (DFS)	The DFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or death from any cause, whichever occurs first.	median follow-up = 4 years
Secondary	Event-free survival (ESF)	The EFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or the date of second neoplasia, or the date of death from any cause, whichever occurs first.	median follow-up = 4 years
Secondary	Acute and late toxicity during the study	The National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.	Throughout treatment completion, up to 4 years
Secondary	Geriatric Assessment	the geriatric questionnaires (CCI & listing comedications, G8, IADL or MMSE) will be completed by a geriatrician or a person trained to geriatric assessment before randomization, at the end of the chemotherapy in arm B or 16 weeks after the randomization in arm A (endocrine treatment only), and then each year during a 4-year follow-up period, for both arms.	at the end of the chemotherapy in arm B or 16 weeks after the randomization in arm A (endocrine treatment only), and then each year during a 4-year follow-up period, for both arms
Secondary	Four-Year Mortality Index for Older Adults(Lee Score)	A 4-year mortality score including items depicting functional status, nutritional status and comorbidities, three key issues in elderly, will be systematically calculated.	At the inclusion
Secondary	Quality of life questionnaire - Core 30 (QLQ-C30)	Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.; The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.; All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	At baseline, week 16, 5 months, 6 months, 1 year, 2 years, 3 years, and 4 years
Secondary	Quality of life questionnaire - Elderly cancer patients (QLQ-ELD15)	The EORTC QLQ-ELD15, a validated HRQOL questionnaire for cancer patients aged greater than or equal to 70 years, is intended to supplement the QLQ-C30.; The QLQ-ELD15 contains 15 items incorporating five scales to assess mobility, family support, worries about future, autonomy and maintaining purpose, and burden of illness. All items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), and are linearly transformed to a 0-100 scale. High scores indicate poor mobility, good family support, less worried about the future, poor autonomy and maintaining purpose, and high burden of illness.	At baseline, week 16, 5 months, 6 months, 1 year, 2 years, 3 years, and 4 years
Secondary	Usefulness of GG by RT-PCR	The prognostic signature of the GG test will be evaluated in an elderly population by comparison to standardized routine histopathological criteria and to the results obtained in the general non elderly population. In the whole cohort (n=2000) results of the GG will be compared to routine histopathological characteristics (pN, histological grade, mitotic count, Ki67 index, determination of Elston and Ellis histological grade) as determined locally or centrally for assessment of patient prognosis.	two weeks after surgery (local histo. and GG test) then after inclusions are performed (central histo.)
Secondary	Cost-effectiveness analysis	In parallel with efficacy analysis, measured by an objective clinical result indicator of state of health, such as the number of year gained (overall survival), costs for the two treatment strategies (endocrine treatment only or endocrine treatment and chemotherapy) in adjuvant systematic treatment will be also estimated. This study should provide information for decision-makers about the incremental efficacy obtained in relation to the incremental cost.	at the end of the chemotherapy in arm B or 16 weeks after randomization in arm A, and then each year during a 4-year follow-up period, for both arms of the group I.